Biophotonic neural probes for studying the brain's immune response

提案编号：1403817P.I.：Roukes，Michael L.标题：研究大脑免疫反应的生物光子学神经探针意义和重要性：加州理工学院被授予研究小型哺乳动物脑机接口免疫反应的新工具。为了开发用于大规模并行刺激和记录的下一代神经探针，并促进先进的脑机接口，我们必须更好地了解大脑对慢性神经植入的免疫反应。现有的最先进的研究通常只允许在动物被牺牲后进行这样的研究。通过这项研究开发的技术将融合纳米生物光子学、可植入神经探针和最先进的微流体的最新进展，以开发、制造和测试下一代技术，该技术将能够实时监测大脑对植入的神经探针的免疫原性反应，包括对药物方案的使用进行实时监测以缓和免疫反应的能力。该项目为培训跨学科科学家和工程师提供了一个难得的机会。在更广泛的推广活动中，研究人员将与加州理工大学的社区科学学院合作，开发一种由iPad促进的K-12学习模块。技术描述：这个为期3年的项目的总体目标将是设计和开发神经化学探针，目标是检测老鼠和其他小动物中的细胞因子和趋化因子。第一年的重点是用光子微环谐振器演示在生理相关浓度(100pg/毫升到10 ng/毫升)下探测感兴趣的目标。第二年的重点将是将光子微环谐振器与蚀刻的微流体与适用于检测特定趋化因子和细胞因子靶标的透析膜进行集成(目标是100 kDa的截止值)。第三年将专注于体内使用的神经化学探针的开发、制造和校准。探针的评估和校准将在含有溶解的趋化因子和细胞因子的琼脂糖制成的“组织模体”中进行。这将包括感兴趣的目标和潜在的干扰因素。我们预计，到这项工作结束时，我们将能够向Siapas(加州理工学院)、Tolias(贝勒医学院)和Laurent(马克斯·普朗克脑研究所)神经科学研究小组提供至少10个校准探针，用于活体使用。在第三阶段，我们还将在纳米系统VLSI联盟(超大规模集成；由PI于2007年共同创立)中开始设计讨论，以将我们基于Caltech的制造工艺转移到我们合作伙伴(CEA/LETI)微纳电子代工厂的标准化生产中。由这项工作资助的研究生将学习使用光学工程、微制造技术和神经科学来生产和使用先进的实验测量系统。除了研究生教育，本科生还将通过加州理工大学的SURF和MURF(暑期和少数族裔本科生研究)计划为该项目做出贡献。与加州理工大学社区科学学院合作开发的K-12学习模块将包括一个低成本、便携式、与iPad接口的折射仪和全内反射演示，用于帕萨迪纳联合学区和洛杉矶联合学区教室。该奖项由两个项目联合颁发-(1)生物光子学，在化学、生物工程、环境和运输系统司(工程局)，(2)生物研究仪器开发，在生物基础设施部(生物科学局)。

Proposal Number: 1403817P.I.: Roukes, Michael L.Title: Biophotonic neural probes for studying the brain's immune responseSignificance and Importance: An award is made to Caltech to engender new tools for studying the immune response to a brain-machine interface in small mammals. To develop the next generation of neural probes for massively parallel stimulation and recording, and facilitate advanced brain-machine interfaces, we must attain a better understanding of the brain's immune response to chronic neural implants. The existing state-of-the-art generally only enables such studies to be performed after an animal has been sacrificed. The technology developed through this research will merge the latest advances in nanobiophotonics, implantable neural probes, and state-of-the-art microfluidics to develop, fabricate, and test next-generation technology that will enable real-time monitoring of the immunogenic response of the brain to implanted neural probes, including the ability to perform real-time monitoring of the use of drug regimens to temper the immune response. The project provides an exceptional opportunity for training interdisciplinary scientists and engineers. In broader outreach, the researchers will collaborate with the Community Science Academy at Caltech to develop an iPAD-facilitated learning module for K-12 use.Technical description: The overarching goal of the 3-year project will be the design and development neurochemical probes targeted to the detection of cytokines and chemokines in mice and other small animals. Year 1 will focus on demonstration of detection of targets of interest at concentrations of physiological relevance (100pg/mL to 10ng/mL) with photonic micro-ring resonators. Year 2 will focus on the integration of photonic micro-ring resonators with etched microfluidics with dialysate membranes appropriate for the detection of specific chemokine and cytokine targets (a 100kDa molecular weight cut-off will be targeted). Year 3 will focus on the development, fabrication, and calibration of neurochemical probes for use in vivo. Evaluation and calibration of probes will be performed in 'tissue phantoms' made from agarose with dissolved chemokines and cytokines. These will include both targets of interest and potential interferents. We anticipate that by the end of this effort we will be able to provide at least 10 calibrated probes to each of the Siapas (Caltech), Tolias (Baylor College of Medicine) and Laurent (Max Planck Institute for Brain Research) neuroscience research groups for use in vivo. In this third phase we will also begin design discussions in the Alliance for Nanosystems VLSI (very-large-scale integration; co-founded by the PI in 2007) to transfer our Caltech-based fabrication processes to standardized production en masse within our partner's (CEA/LETI) micro-/nano-electronics foundry. The graduate student funded by this effort will learn to employ optical engineering, microfabrication techniques, and neuroscience in order to produce and employ advanced experimental measurement systems. In addition to graduate student education, undergraduate students will contribute to the project through the SURF and MURF (summer- and minority- undergraduate research) programs at Caltech. The K-12 learning module developed as an outreach effort in collaboration with the Community Science Academy at Caltech will include a low-cost, portable, iPAD-interfaced refractometer and demonstration of total internal reflection for use in Pasadena Unified School District and Los Angeles Unified School District classrooms.This award is being made jointly by two Programs- (1) Biophotonics, in the Division of Chemical, Bioengineering, Environmental and Transport Systems (Engineering Directorate), and (2) Instrument Development for Biological Research, in the Division of Biological Infrastructure (Biological Sciences Directorate).